CLIENT BENEFITS
Topics:
1.
Mechanistic investigations, kinetic modeling
2.
Reaction parameter screening
3.
Separation unit operations evaluation: filtration, distillation,
spray-drying, drying
4.
Formulation Screening
5.
Process safety evaluation
6.
Crystallization robust process development
7.
Scale-up investigations; analysis of the impact of the equipment
on process results; mass and heat transfer
8.
Cost estimates
9.
Principal Component Analysis (PCA) for production troubleshooting
1. Mechanistic investigations, kinetic modeling
Project:
Mechanistic investigations in a synthetic step of an API intermediate
Contribution:
Selected, and designed on-line analytical method (FT-IR); analyzed
in-process data, corroborated with off-line (HPLC) measurements, and
developed kinetic model
Results:
The process chemistry team was able to confirm one of two proposed
mechanisms. A preliminary PAT method was designed.
2.
Reaction parameter screening
Project:
Catalytic reaction parameter rapid screening; five possible
significant factors were identified: substrate concentration,
solvent, temperature, catalyst type and level
Contribution:
Statistically designed an aggressive ten-experiment matrix, using
yield and purity as process results. Established that concentration
and temperature were statistically much more important than the other
three parameters
Results:
The process chemistry team rapidly selected suitable parameters
for this catalytic reaction, and was able to quickly design a
synthetic route for the target molecule (project in phase I)
3.
Separation unit operations evaluation: filtration, distillation,
spray-drying, drying
Project:
Synthetic process optimization, including comparison between a
telescoped and a stepwise version
Contribution:
Executed distillation calculations, evaluated a solvent “switch”
step present in the telescoped process, and recommended the use of a
modified stepwise process
Results:
Designed an improved, robust process; the team was able to scale-up
the process to the pilot plant successfully (several batches in
several campaigns)
Project:
Scaleable formula design for a semi-solid product, including
novel ingredients
Contribution:
Selected suitable powder mixer; designed, executed, and analyzed an
nine experiment matrix evaluating: agitation speed, chopper time,
batch size, mixer angle, and liquid ingredient addition rate
Results:
Designed a “base-line” process that the formulators team
used to screen approximately one hundred formulations. The process
was then optimized, and readied for scale-up
5.
Process safety evaluation
Project:
Exothermic, heterogeneous process to be scaled-up to the kilo-lab
and the multipurpose pilot-plant
Contribution:
Designed, executed and analyzed RC1™ (reactor calorimeter)
experiments. Executed heat transfer calculations (media temperature
evolution in time), using the calorimetric results generated, and
equipment data. Made recommendations for batch size, and agitation
conditions in the large scale reactors
Results:
The kilo-lab and pilot plant teams were able to successfully scale-up
the process, as scheduled
6.
Crystallization robust process development
Project:
Crystallization process to be scaled-up in order to produce 100
kg of API
Contribution:
Statistically designed experiments aimed at to establish critical
process parameters. Developed process, and designed process
validation experiments, confirming its robustness. From in-process
crystallization data, and mixing calculations, developed particle
size model, quantifying the dependence between particle size and
mixing parameters
Results:
The 100 kg of API produced in kilo-lab and pilot plant campaigns
passed all specifications, including solid state properties
(polymorph, morphology)
7.
Scale-up investigations; analysis of the impact of the equipment on
process results; mass and heat transfer
Project:
Solid-liquid exothermic process to be scaled-up to the
multipurpose pilot-plant
Contribution:
Evaluated the safety of the process (as described above). Using
mixing calculations, designed experiments to model the behavior of
the slurry upon scale-up. Designed process, and made recommendations
for batch size and agitation conditions in the plant reactor
Results:
The pilot plant team was able to scale-up the process successfully,
on time
8.
Cost estimates
Project:
Synthetic route selection, based on two routes using different
key raw materials. Several cost factors exhibit probabilistic
evolution in time
Contribution:
Developed cost model, and executed Monte Carlo simulations to
determine cost ranges for each route. The calculation results
(standard deviation) were also useful to define cost improvement
objectives
Results:
The project team was able to make a meaningful decision quickly
9.
Principal Component Analysis (PCA) for production troubleshooting
Project:
Sudden out-of-specification drug product batches in complex
manufacturing process
Contribution:
Executed multivariate data analysis to determine main factors
(principal components) responsible for batch failure. Identified
three such factors, consistent with the hypothesis proposed by the
team to explain batch failure
Results:
The project team used the PCA results to understand better some of
the complex interactions between process parameters and drug product
quality attributes